The excitatory amino acid, glutamate, is a leading candidate to be the neurotransmitter at the majority of excitatory synapses in the vertebrate central nervous system and is postulated to play roles in a variety of physiological and pathological processes, ranging from learning and memory to neuron degeneration in several neuropsychiatric disorders. Despite this importance, the factors involved in the short term regula- tion of responses at glutamate receptors are not well understood. Recently it has been found that certain glutamate receptors undergo a profound use dependent decline in responsiveness during repeated or pro- longed applications of agonists. This "desensitization' process thus rep- resents a potentially important mechanism by which glutamate responses may be modulated. In this application, studies are designed to use vol- tage clamp and single channel recording techniques to investigate the process and functional significance of desensitization occurring at the non-N-methyl-D-aspartate (non-NMDA) class of glutamate receptors in cul- tured postnatal rat hippocampal neurons. Specific experiments will examine factors involved in the use dependent decay of glutamate/quis- qualate currents, whether the decline in responsiveness is mediated by an ion channel block or conformational change desensitization mechanism and whether the process is subject to modulation by second messengers and lectins. Subsequent studies will use the results of initial experiments to address whether desensitization plays a role in the synaptic phy- siology of glutamate and whether the process has relevance to the action of glutamate as a neurotoxin. The proposed studies have the potential to shed light on the regulation of glutamate responses and on ways to alter glutamate functions in the treatment of neuropsychiatric disorders.